CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids.
CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids.
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DOI：
10.1186/s12931-022-02119-1
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发表时间：
2022-07-28
影响因子：
5.8
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中科院分区：
文献类型：
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CCAAT/增强子结合蛋白D（CEBPD）是一种多效性糖皮质激素应答性转录因子，调节炎症反应。与哮喘相关的是，CEBPD在气道平滑肌（ASM）中的表达随着糖皮质激素暴露而增加。我们试图通过测量敲除CEBPD后观察到的变化及其对哮喘相关ASM功能的影响来表征CEBPD介导的ASM对糖皮质激素暴露的转录组学反应。用CEBPD或非靶向（NT）siRNA转染来自4名供体的原代ASM细胞，并暴露于溶剂对照、布地奈德（100 nM，18 h）、TNFα（10 ng/ml，18 h）或布地奈德和TNFα。随后，使用RNA-Seq测量基因表达水平，并获得暴露与媒介物和敲低与对照条件的成对差异表达结果。进行加权基因共表达分析以鉴定在各种实验条件下具有相似表达模式的基因组（即，CEBPD敲低状态，暴露）。在至少一次暴露下，CEBPD敲低改变了3037个基因的表达（q值< 0.05）。共表达分析确定了分别与CEBPD敲低状态、TNFα暴露状态以及两者相关的197、152和290个基因。JAK-STAT信号通路基因，包括IL 6 R和SOCS 3，是受TNFα和CEBPD敲低影响的基因。免疫印迹分析显示，布地奈德诱导的IL-6 R蛋白表达和增强的IL-6诱导的STAT 3磷酸化水平被ASM中的CEBPD敲低所减弱。CEBPD部分通过调节IL-6受体信号传导来调节ASM中的糖皮质激素应答。在线版本包含补充材料，可通过10.1186/s12931-022-02119-1获得。
CCAAT/Enhancer Binding Protein D (CEBPD), a pleiotropic glucocorticoid-responsive transcription factor, modulates inflammatory responses. Of relevance to asthma, expression of CEBPD in airway smooth muscle (ASM) increases with glucocorticoid exposure. We sought to characterize CEBPD-mediated transcriptomic responses to glucocorticoid exposure in ASM by measuring changes observed after knockdown of CEBPD and its impact on asthma-related ASM function. Primary ASM cells derived from four donors were transfected with CEBPD or non-targeting (NT) siRNA and exposed to vehicle control, budesonide (100 nM, 18 h), TNFα (10 ng/ml, 18 h), or both budesonide and TNFα. Subsequently, RNA-Seq was used to measure gene expression levels, and pairwise differential expression results were obtained for exposures versus vehicle and knockdown versus control conditions. Weighted gene co-expression analysis was performed to identify groups of genes with similar expression patterns across the various experimental conditions (i.e., CEBPD knockdown status, exposures). CEBPD knockdown altered expression of 3037 genes under at least one exposure (q-value < 0.05). Co-expression analysis identified sets of 197, 152 and 290 genes that were correlated with CEBPD knockdown status, TNFα exposure status, and both, respectively. JAK-STAT signaling pathway genes, including IL6R and SOCS3, were among those influenced by both TNFα and CEBPD knockdown. Immunoblot assays revealed that budesonide-induced IL-6R protein expression and augmented IL-6-induced STAT3 phosphorylation levels were attenuated by CEBPD knockdown in ASM. CEBPD modulates glucocorticoid responses in ASM, in part via modulation of IL-6 receptor signaling. The online version contains supplementary material available at 10.1186/s12931-022-02119-1.
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DOI：
10.1038/nrrheum.2015.169
发表时间：
2016-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
Kalliolias GD;Ivashkiv LB
通讯作者：
Ivashkiv LB
影响因子：
30.5
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影响因子：
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作者：
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通讯作者：
Garbe, Paul
影响因子：
24.3
作者：
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通讯作者：
Teague, W. Gerald
DOI：
10.1016/j.jaci.2012.03.018
发表时间：
2012-08
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
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通讯作者：
National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program (SARP)